Study: In heroin addiction, glial cells play key roles in regulating the motivation for the drug

Findings suggest these specialized cells help rewire the addicted brain

“In the addiction field, most neuroscientists focus on neurons. Very rarely have they studied glial cells in psychiatric diseases.”

David Dietz, PhD, Associate professor, Department of Pharmacology and Toxicology

Jacobs School of Medicine and Biomedical Sciences

BUFFALO, N.Y. — Scientists studying addiction know that
heroin and other opioids induce plasticity in brain cells. Now,
University at Buffalo researchers have made the novel discovery
that in certain types of brain cells, drug-induced plasticity can
work to reduce, rather than boost, motivation for heroin.

By providing new insights into how addiction changes the brain,
the research could lead to novel approaches to treatments and
potential new targets besides neurons.

“Most therapies have focused on the blocking or activating
of receptors that bind drugs like heroin,” explained David
Dietz, PhD, senior author of the paper and associate professor in
the Department of Pharmacology and Toxicology in the Jacobs School
of Medicine and Biomedical Sciences at UB. “While that
approach may be effective in the short-term, it doesn’t get
to the fundamental problem of what is addiction and how to prevent
it, as well as prevent relapse.”

Published online last month in Neuropsychopharmacology, the
paper describes how glial (non-neuronal) cells regulate both
cellular and behavioral responses to heroin.

“Not much is known about glial cells in the context of
addiction” said Dietz, a faculty member with UB’s
neuroscience program. “In the addiction field, most
neuroscientists focus on neurons. Very rarely have they studied
glial cells in psychiatric diseases. This work demonstrates an
essential role of glia in addictive behaviors, and offers us the
ability to provide a new set of targets for future therapies toward
the treatment of addiction.”

Dietz and his colleagues decided to study the potential role of
glial cells in addiction when they found that RNA sequencing of
tissue from heroin-addicted animals revealed changes in genes that
are traditionally markers for a type of glial stem cell called
oligodendrocyte precursor cells or OPCs.

Opiates and the prefrontal cortex

The research is likely the first to investigate how opiates
affect adult OPCs in the brain’s prefrontal cortex, which is
involved in complex cognitive behaviors and is a main target of
addictive drugs.

“We found that many of the genes regulated by heroin
aligned with the profile of OPCs, so something was going on with
them,” he said.

OPCs, he explained, are cells that often become myelin,
which is critical for efficient communication between neurons.

Dietz collaborated with his colleague Fraser Sim, PhD, associate
professor in the Department of Pharmacology and Toxicology in the
Jacobs School, co-author on the paper. In 2014, Sim identified one
of the genes, SOX10, as a “master switch” for the
differentiation of these stem cells towards myelination.

To determine what was happening when genes encoding OPCs were
exposed to heroin, the scientists overexpressed them in addicted
laboratory animals using viral gene therapy.

Compensatory effect

The result was surprising: when either of the two genes, SOX10
or BRG1, was overexpressed, the animals’ motivation to take
the drug was reduced.

“To our surprise, it reduced their drug-taking
behavior,” said Dietz. “It looks like the brain is
trying to reconnect and possibly readapt myelin to normalize
function, although that would need to be directly tested in future
studies.”

One way to think of what may be happening, he explained, is to
imagine that the brain is responding to exposure to drugs of abuse
by attempting to reconnect with the brain’s other reward
centers.

“As with any part of the body that sustains an insult, it
seems that the addicted brain is trying to fix what went
wrong,” he said. “Our hypothesis is that after exposure
to heroin, the brain starts to upregulate OPCs in an attempt to fix
the altered connectivity that occurs in the addicted states. It is
possible that when we facilitated OPCs, we may have reversed some
of the disconnect between the prefrontal cortex and the
brain’s other reward regions.”

The research was funded by the National Institute on Drug Abuse
of the National Institutes of Health.

Along with Dietz and Sim, other co-authors are: J.A. Martin, A.
Caccamise, C.T. Werner, R. Viswanathan, J.J. Polanco, A.F. Stewart,
S.A. Thomas, all of the Department of Pharmacology and Toxicology
in the Jacobs School.